Results Post-procedure, the metallic EES group was more symmetric and concentric than the BVS group. Only 8.0% of the BVS arm and 20.0% of the metallic EES arm achieved optimal scaffold/stent expansion (p < 0.001). At 1 year, there was no difference in the DoCE between both devices (BVS 5.2% vs. EES 3.1%; p = 0.29). Post-procedural devices asymmetry and eccentricity were related to higher event rates while there was no relevance to the expansion status. Subsequent multivariate analysis identified that post-procedural AI >0.30 is an independent predictor of DoCE (hazard ratio: 3.43; 95% confidence interval: 1.08 to 10.92; p = 0.037).

Bioresorbable vascular scaffolds (BVS) (Absorb BVS; Abbott Vascular, Santa Clara, California) have emerged as a novel technology with several potential advantages compared to permanent metallic stents in the treatment of coronary artery disease (1). Data from randomized control trials showed that the scaffold efficacy is noninferior to the available metallic drug-eluting stent (DES) (2,3). However, the use of BVS remains limited to noncomplex coronary lesions because their limitations stemming from the inherent differences in the mechanical properties of polymeric material of BVS compared to metallic DES (e.g., a lesser radial strength) (4).

Previously, difference in acute stent performance between the Absorb BVS and metallic everolimus-eluting stent (EES) has been investigated (5). In the absence of specific intracoronary imaging guidance, BVS exhibited higher device asymmetry and eccentricity than metallic EES post-implantation as assessed by intravascular ultrasound (IVUS), without detectable impact on major adverse cardiac event rate at 6 months (5). However, the understanding of the prognostic value of the device performance such as expansion, eccentricity and asymmetry indices in clinical practice remains limited mainly due to the observational nature of the studies, use of old stent platforms (6), small sample sizes (7), and short follow-up duration (6,7).

It is of interest to investigate the acute performance of a new scaffold/stent platform and their relationships to device-oriented composite endpoint (DoCE) in a larger sample size and in the context of a randomized trial (3). The aim of this study was to assess the impact of post-procedural scaffold/stent asymmetry, expansion, and eccentricity indices on early and late clinical events treated either with a metallic or polymeric devices.

Methods

Study population

The ABSORB II (A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions) trial is a prospective, single-blinded, randomized, active controlled trial. The study included 501 patients with de novo coronary lesions, randomized in 2:1 ratio to receive either treatment with an everolimus-eluting bioresorbable scaffold (Absorb BVS) or with an everolimus-eluting metallic stent (Xience, Abbott Vascular, Santa Clara, California). The details of inclusion and exclusion criteria have been described previously (8). For the purpose of the study, only patients with post-procedural IVUS were included. Of 501 patients, 31 patients were excluded due to the reasons listed in Figure 1. Consequently, the total 470 patients with post-procedural IVUS were included in the analyses.

Study device

The details of the study device (Absorb BVS) have been described previously (8,9). In brief, the balloon-expandable Absorb scaffold comprises a poly-L-lactide backbone coated with an amorphous drug-eluting coating matrix composed of poly-D,L-lactide polymer containing everolimus 100 μg/cm2. The control device was the second-generation EES Xience, which is a balloon-expandable metallic stent, manufactured from a flexible cobalt chromium alloy, and coated with a thin nonadhesive, durable, biocompatible acrylic, and fluorinated everolimus-releasing copolymer (8). The Xience stent and Absorb scaffold share the same basic MULTI-LINK design, and both devices are similar in terms of drug, drug dose density, and elution profile.

Imaging acquisition and analysis

Quantitative angiographic assessment

In each patient, the scaffold/stent segments and the periscaffold/stent segments (defined by a 5 mm length proximal and distal to the scaffold edge) were analyzed by quantitative coronary angiography (QCA) pre- and post-procedure. QCA was performed at an independent core lab (Cardialysis BV, Rotterdam, the Netherlands) with the CAAS system (CAAS 5.10, Pie Medical BV, Maastricht, the Netherlands). The QCA measurements details are described elsewhere (8,10–12).

Pre- and post-procedural IVUS analysis

The methods of quantitative IVUS have been previously reported (3,8). The pre-procedure segments were defined by coregistration with post-procedural IVUS using identical landmarks such as side-branches and calcium locations. Matching was done using dedicated software (IvusOCTRegistration, Division of Image Processing, Leiden, the Netherlands). Pre-treatment reference segments were selected as sites with the least amount of plaque proximal and distal to the minimal lumen area (MLA) sites prior to the takeoff of any major side branches. The scaffold/stent segments were identified by the first and the last cross-sectional IVUS frame in which the scaffold/stent struts could be identified and/or where the proximal or distal metallic markers could be identified. The post-procedural region of interest was the segment beginning at 5 mm distal of the scaffold/stent segment extending to the proximal 5 mm of the scaffold/stent segment (13).

IVUS parameter definitions

Calcification on pre-procedural IVUS appears as bright echoes with acoustic shadowing of the deeper arterial structures. Location and circumferential distribution of calcium were quantified on grayscale IVUS. The largest continuous arc of calcium and summed arc of calcium at the site of the pre-interventional lumen area were measured in degrees with a protractor centered on the lumen. Remodeling was assessed by the remodeling index, expressed as the vessel area at the MLA site divided by the average vessel area of the proximal and distal reference segment. Three remodeling categories were defined as follows: positive remodeling, remodeling index >1.00; intermediate remodeling, remodeling index 0.88 to 1.00; and negative remodeling, remodeling index <0.88 (14).

Incomplete apposition was defined as 1 or more scaffold/stent struts separated from the vessel wall. The acute device performance was evaluated by 3 parameters. First, asymmetry index (AI) was calculated per lesion (1 − minimum scaffold/stent diameter/maximum scaffold/stent diameter throughout an entire pullback) (5,15). Scaffold/stent diameter in each cross-section were measured through each gravitational center for each sectorial degree (16); minimal scaffold/stent diameter was the minimal value of minimal scaffold/stent diameter throughout scaffold segment, and maximal scaffold/stent diameter was the maximal value of maximal scaffold/stent diameter throughout scaffold/stent segment. Therefore, the minimum scaffold/stent diameter and maximum scaffold/stent diameter could derive from different cross sections in the scaffold segment. A lesion was characterized as asymmetric when the value of AI was over 0.3 (6). Conversely, a lesion with AI ≤0.3 was defined as a symmetric lesion. The AI cutoff of 0.3 was derived from the MUSIC study in which the symmetric stent expansion was defined as a ratio of minimum lumen diameter and maximum lumen diameter throughout an entire pullback ≥0.70 (which corresponds to AI of 0.30) had favorable angiographic results at 6 months’ follow-up. Second, scaffold/stent expansion index was calculated by the ratio of minimum scaffold/stent area (MSA) to the average reference lumen area (RLA) (6). The optimal scaffold/stent expansion (OSE) was defined according to criteria of the MUSIC study (6) as MSA ≥90% of the average RLA or ≥100% of lumen area of the reference segment with the lowest lumen area. If MSA ≥9 mm2, OSE was defined as MSA ≥80% of the average RLA. Third, eccentricity index (EI) was calculated as a parameter for the circularity of the cross section using the formula of minimal scaffold/stent diameter divided by maximal scaffold/stent diameter. Therefore, the calculation of minimal and maximal scaffold/stent diameter was derived from the same cross-section (5,6,15). The IVUS cross sections with the lowest EI value per pullback were used for the analysis. A lesion with EI ≥0.7 was defined as concentric while EI <0.7 was defined as eccentric lesion (17,18).

Clinical endpoints and definition

In the present analysis, the primary clinical outcome was a device-oriented composite endpoint (DoCE) at 1 year, defined as a composite of cardiac death, myocardial infarction (MI) (defined by Q-wave and non–Q-wave MI from nonattributed to nontarget vessels), and ischemia-driven target lesion revascularization by coronary bypass graft or percutaneous coronary intervention. All clinical endpoint definitions are described in the Online Appendix. Definite and probable scaffold/stent thrombosis was adjudicated according to the Academic Research Consortium definitions (19). An independent clinical events committee adjudicated all clinical outcomes.

Statistical analysis

All statistical analyses were performed using SAS release 9.1 (SAS Institute Inc., Cary, North Carolina) or IBM SPSS Statistics, version 23.0 (IBM Corp., Armonk, New York). QCA and IVUS were analyzed per lesion. All continuous variables were presented as mean ± SD or median (interquartile range) as appropriate. Unpaired t test or nonparametric Mann-Whitney U test was used for comparisons of continuous variables and chi-square test was used for categorical variables. For lesion-level data, a model with a generalized estimating equation approach was used to compensate for any potential cluster effect of more than 1 vessel scaffold/stent implantation in the same patient and presented as least-squares mean with 95% confidence interval (CI). Differences were considered to be statistically significant if the p value was <0.05.

The endpoints analyses were performed according to the intention-to-treat principle and presented at a patient-level. Whenever a patient received more than 1 lesion treatment, the lesion with the lowest scaffold/stent EI was selected as representative of that patient. One-year clinical outcomes according to post-procedural asymmetry, optimal stent expansion, and eccentricity status were separately compared by the log-rank test. A multivariate Cox proportional hazards model was performed to determine the independent determinants of DoCE. A multivariate Cox proportional hazards analyses was performed to determine the independent determinants of DoCE. The first model was constructed using significant variables in the univariate analysis. The second model was constructed with forward stepwise Cox multivariable regression analysis, entry, and removal criteria of 0.05 and 0.10, respectively. Adjusted hazard ratio (HR) with 95% CI was calculated. The proportional hazards assumption of the Cox regression model was checked by using time-dependent Cox models. If any of the pre-defined IVUS parameters showed statistical significance from logistic regression analysis, receiver-operating characteristic curve and c-index were used to justify the cutoff value. The sensitivity analysis are detailed in the Online Appendix.

Results

Clinical, angiographic results and procedural characteristics

Of the 470 patients, 308 patients (330 lesions) were randomly assigned to BVS arm whereas 162 patients (176 lesions) were assigned to metallic EES arm. Baseline clinical, angiographic results and procedural characteristics are detailed in Table 1. There were no significant differences in the patient’s baseline characteristics comparing both devices. Patients treated with the BVS had a higher post-procedural diameter stenosis and lower acute gain compared to the metallic EES. The post-dilation balloon size and pressure in the BVS group were lower than the metallic EES.

Baseline Clinical and Angiographic Findings and Procedural Details Based on Device Type

IVUS findings pre- and post-procedure between BVS and metallic EES

IVUS findings between the 2 devices are tabulated in Table 2. Pre-procedure, the presence of calcium and the sum arc of calcium were similar for both devices. Pre-procedural lumen EI of metallic EES arm was lower than the BVS arm (0.59 [IQR: 0.57 to 0.61] vs. 0.61 [IQR: 0.60 to 0.62]; p = 0.041), whereas the pre-procedural AI was not significantly different. Post-procedure, MSA measured 4.87 (IQR: 4.72 to 5.02) mm2 in the BVS group and 5.72 (IQR: 5.49 to 5.94) mm2 in the metallic EES group (p < 0.001). Lesions treated with BVS were more eccentric (27.3% vs. 4.5%; p < 0.001) and asymmetric (62.1% vs. 29.5%; p < 0.001) than lesions treated with metallic EES. Among 506 lesions, the scaffold/stent expansion index was calculated in 425 lesions, while in the remaining 71 lesions the scaffold/stent expansion indices could not be calculated due to the presence of side branches both at the proximal and distal edges of the scaffold/stent. Notably, only 8.0% in BVS arm and 20.0% in metallic EES could achieve optimal scaffold stent expansion (p < 0.001).

Intravascular Ultrasound Findings Pre- and Post-Implantation According to Implanted Devices

Device-oriented composite endpoint at 1 year as stratified by IVUS parameters

At 1 year, the DoCE rates were 5.2% in BVS and 3.1% in EES, respectively (p = 0.29). DoCE and the components as stratified by the pre-defined IVUS parameters are shown in Table 3. The DoCE rates were similar between the OSE group and suboptimal stent expansion group (4.2% vs. 4.4%; p = 0.93). When stratified by the AI, the asymmetric group was associated with a higher risk of DoCE than the symmetric group. As showed in Figure 2, DoCE occurred in 4 of 224 patients in the symmetric group, whereas it occurred in 17 of 246 patients in the asymmetric group (1.8% vs. 6.9 %; p = 0.007). A higher event rate in the asymmetric group was primarily driven by a higher incidence of MI (majority was periprocedural MI), while the incidence of cardiac death, definite/probable scaffold/stent thrombosis were not significantly different between both groups. However, upon stratification by the EI, eccentric lesions had higher rates of DoCE, target lesion revascularization, and definite/probable scaffold/stent thrombosis than concentric lesions (Table 3). Of note, as showed in Figure 2, all eccentric lesions belonged to the asymmetric lesions group.

Incidence of DoCE at 1-Year Follow-Up According to the Criteria of Optimal Expansion, Asymmetry, and Eccentricity of Device Post-Implantation

IVUS predictors for DoCE after scaffold/stent implantation

Table 4 shows the univariate predictors of DoCE after scaffold/stent implantation for the entire population and each device. Subsequent multivariate analysis (Table 5) from both 2 models identified that AI >0.30 after implantation was an independent predictor for the occurrence of DoCE (adjusted HR: 3.43; 95% CI: 1.08 to 10.92; p = 0.037), whereas there was no consistency of the statistical significances of pre-procedural diameter stenosis, pre-procedural negative remodeling lesion, total stent length and overlapping implantation across the 2 models. The cutoff of 0.30 was justified by receiver-operating characteristic curve analysis and demonstrated in Online Figure 1.

Multivariate Analysis for Predictors of DoCE After Scaffold/Stent Implantation

Upon comparison of patients with asymmetric versus symmetric lesions: there was a lower prevalence of diabetes (22% vs. 27.2%; p = 0.04); lesions were more complex (type B2/C) and more moderate to severe calcification; the reference vessel diameter was smaller and the lesion length was longer in the asymmetric subgroup, respectively. Furthermore, the baseline MLA, post-procedural MSA, and expansion index were lower in the asymmetric group, along with a higher prevalence of eccentric device after implantation (38.1% vs. 0%; p < 0.001; respectively) (Online Table 1).

The interaction between the subgroup and asymmetry status was performed to confirm if the influence of asymmetry on adverse events was consistent among the subset of patients. As shown in Figure 3, post-implantation device asymmetry compared with symmetry was consistent in all subgroups. As the sample size was small for most subgroups, caution should be used in the interpretation of these results and in drawing conclusions.

Discussion

The present study investigated the impact of acute scaffold/stent performance of BVS and the second-generation DES on clinical outcomes. The current analyses suggested that post-procedural AI >0.30 was associated with adverse clinical outcomes.

Importance of AI over expansion index: Are these 2 parameters similar in evaluating optimal deployment?

MSA and expansion index have been widely used as indicators of optimal scaffold/stent expansion whereas there was less attention dedicated to post-implantation device asymmetry and eccentricity. Indeed, these parameters aim to evaluate the optimal device performance, so called “expansion.” The present study showed that post-implantation device asymmetry (AI >0.30) is one of the predictors of DOCE while MSA, expansion index, and EI were not. Furthermore, the asymmetric lumen has worse outcomes especially in patients with suboptimal expansion. However, a nonsignificant p value for interaction (p = 0.34) suggested that this influence was not different in patients with or without optimal expansion.

Thus, the current study suggested that a single variable of the expansion index is not enough to predict future events without taking into consideration the homogeneity of the stent/scaffold expansion and it seemed that AI was a more discriminant parameter compared to the EI.

The discrepancy of the present study with previous publications could be explained by the following reasons. First, the criteria of optimal stent expansion used in previous reports varied considerably. For example, the optimal stent expansion criteria in some studies depended on the discretion of the treating operator (20,21). Some used absolute value of MSA ≥5.0 mm2(22) or the ratio of MSA to cross-section area of the fully inflated post-dilation balloon (23). Additionally, the outcomes measured in each study were also different. Second, the criteria applied to evaluate the optimal device expansion in the present study was based on IVUS-guidance stent implantation trial while IVUS in the ABSORB II trial was only documentary. Third, the current analysis was a comparison between metallic EES and BVS in a randomized design, while previous trials were conducted in the first-generation DES platform, mostly in nonrandomized studies, only with post-procedural IVUS and shorter clinical follow-up (6 months).

How does device asymmetry contribute to DoCE?

The present analysis showed that AI >0.30 is associated with a high rate of MI and primarily represented by periprocedural MI, which could potentially be explained by disruption of the laminar flow and induced flow disturbances in asymmetric lesions. Low shear stress could induce platelet aggregation, microthrombi formation with potential embolization, leading to micromyocardial necrosis (24).

Additionally, the present study also showed a higher target lesion revascularization in the eccentric device subgroup. Potential explanations could be the following. First, the pharmacokinetic models have shown that substantial inhomogeneities in drug concentration exist for different strut placements and geometry (25). An inhomogeneous strut distribution in eccentric and asymmetric lesions may cause lower local drug concentration, subsequent neointimal hyperplasia and restenosis that could explain the increased target lesion revascularization incidence: Second, the heterogeneous EES due to the asymmetric and eccentric lumen may further accentuate the plaque eccentricity and further amplify the low EES effect. The low EES area is at high risk for rapid worsening plaque distribution (26) that may result in more restenosis at follow-up.

When the univariate analysis was performed separately in the metallic EES arm and Absorb arm (Table 4), AI >0.30 did no longer demonstrated statistical significance in the metallic EES arm. As shown in Figure 3, the influence of asymmetric lumen on clinical outcomes tended to be more emphasized in the Absorb arm (HR: 9.19; 95% CI: 1.19 to 70.60) than in the metallic EES arm (HR: 1.51; 95% CI: 0.25 to 9.35) although the p value for interaction failed to reach statistical significance (p = 0.06). Therefore, to avoid post-implantation device asymmetry, intravascular imaging may have an important role in the detection and correction of these morphologic abnormalities. Recently, Hong et al. (27) reported that IVUS-guided EES implantation, compared with angiography-guided stent implantation, resulted in significantly lower rates of major adverse cardiac events. It remains to demonstrate whether post-procedural eccentricity and asymmetry could be corrected by aggressive post-dilation or whether this strategy should be avoided and prevented by an aggressive lesion preparation. Mattesini et al. (15) showed that both BVS and second-generation DES could achieve similar asymmetry, eccentricity indices, minimal and mean scaffold/stent areas with optical coherence tomography guidance to achieve optimal expansion at the discretion of the treating operator by further post-dilation. Also, the diameter and pre-dilation balloon pressure were higher in the ABSORB compared to the DES group. In addition, post-dilation balloon pressure was higher in the ABSORB group while the post-dilation balloon diameter was similar. Aggressive lesion preparation in combination with a high pressure post-dilation may have corrected the pre-procedural eccentricity and asymmetry. Further research with a large clinical trial assessing the role of intravascular imaging guidance for lesion preparation and device post-dilation to achieve optimal scaffold/stent expansion is of interest to clarify its impact on clinical outcomes.

Study limitations

First, multivariate analyses could not be performed extensively due to limited number of events. In the present analysis, 2 multivariate models contributed different independent predictors of DoCE, nevertheless, AI >0.30 is the only variable that remains significant in the analyses. Hence findings should be interpreted with caution and are hypothesis generating in nature. Second, the relatively simple lesions characteristics might have limited our ability to generalize our findings, especially to patients with complex lesions that we commonly see in the daily clinical practice. Third, the expansion index was evaluated in 391 patients due to missing data in 79 patients (16.8%). Fourth, because the 1-year follow-up of the ABSORB II trial is purely clinical, we could not evaluate the restenosis process on angiography or IVUS and relate the asymmetry and eccentricity assessment to neointimal hyperplasia.

Conclusions

In this ABSORB II IVUS substudy, asymmetry, expansion, and eccentricity was used to investigate its relationship to the incidence of DoCE. Post-procedural device asymmetry and eccentricity were related to a higher event rates while the expansion status was not. Post-intervention AI >0.30 should be avoided to reduce asymmetry or eccentricity-related complication, although the results are hypothesis generating.

Perspectives

WHAT IS KNOWN? Minimal stent area and expansion index have been widely used as indicators of optimal scaffold/stent expansion whereas the impact of post-implantation device asymmetry and eccentricity on clinical events is unclear.

WHAT IS NEW? The current analyses suggested that post-procedural AI >0.30 was associated with adverse clinical outcomes.

WHAT IS NEXT? It remains to demonstrate whether post-procedural eccentricity and asymmetry could be corrected by aggressive post-dilation or whether this strategy should be avoided and prevented by an aggressive lesion preparation.

Appendix

Appendix

For an expanded Methods and Results sections as well as a supplemental figure and table, please see the online version of this article.

Footnotes

The ABSORB II trial was sponsored by Abbott Vascular. Dr. Lang has served as a consultant for Abbott Vascular, Medtronic, Biotronik, and Edwards Lifesciences. Dr. Egred has served as a proctor for Abbott Vascular; and has received honoraria for bioresorbable vascular scaffold workshops. Dr. Lesiak has received payments as an individual for advisory board and speaker honoraria from Abbott Vascular. Dr. Chevalier has served as a consultant for Abbott Vascular. Dr. Serruys has served on the international advisory board for Abbott Vascular; and on the advisory board for Boston Scientific. Dr. Onuma has served on the international advisory board for Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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(2001) American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol37:1478–1492.